Abstract The longstanding issue addressed in this proposal is: ?How can we improve the poor and highly variable bioavailability of oral anticancer therapy?? Our research proposal seeks to characterize a strategy to improve the problematic disposition profile of ibrutinib, a recently-approved targeted therapy that is highly effective in cancers driven by B-cell proliferation, through the use of pharmacologic inhibition of CYP3A, the major drug-metabolizing enzyme family for ibrutinib and many other oral anticancer agents. In this proposal, we (i) identify CYP3A metabolism as the primary cause of ibrutinib?s remarkably low bioavailability and (ii) evaluate the impact of pharmacological inhibition of CYP3A on ibrutinib PK/PD and efficacy in preclinical models. We have identified a strategy to improve the disposition profile of ibrutinib through inhibition of CYP3A. Utilizing mice genetically engineered to lack CYP3A expression, we determined that CYP3A limits the oral bioavailability of ibrutinib and that it is feasible to increase ibrutinib bioavailability through pharmacologic inhibition of CYP3A with cobicistat, a drug used in combination with certain oral HIV drugs to improve pharmacokinetics (PK). In Aim 1, we will establish a computational population PK model to determine an optimal low dose of ibrutinib that, when combined with cobicistat, achieves PK and pharmacodynamics (PD) similar to higher doses of ibrutinib with established efficacy. As the relationship between increasing bioavailability and decreasing interpatient PK variability is well-established, a strategy to increase the bioavailability of ibrutinib is expected to decrease ibrutinib?s significant interpatient PK variability. More consistent ibrutinib PK could prevent levels of drug that are too high or too low which could cause side effects or treatment failure respectively. The use of cobicistat to improve the disposition profile of ibrutinib is only feasible if combination treatment does not compromise the therapeutic efficacy of ibrutinib. In Aim 2, we will characterize the impact of our strategy on the efficacy of ibrutinib in models of B-cell malignancies. Demonstration that our strategy is not antagonistic will inform the prospective design of a phase 1b trial evaluating this strategy through a collaborative effort with a hematologist. The successful completion of this proposal will aid in achieving our long-term goal to decrease adverse events associated with ibrutinib, as well as other oral anticancer drugs, through the improvement of their PK properties. The proposed studies will be completed during the doctoral graduate studies of Eric Eisenmann in the Experimental Cancer Pharmacology Laboratory (ECPL) under the guidance of Drs. Alex Sparreboom and Sharyn Baker at The Ohio State University College of Pharmacy (OSU-COP). This project will provide Eric with opportunities to learn new techniques and critical scientific communication skills. The ECPL and Ph.D. program at OSU-COP will support the success of Eric and this project by providing resources and a structured training environment to facilitate progression towards becoming an independent researcher.